tbuckley/cabot-search huggingface dataset:
Phase I study of drug-resistant immunotherapy (DRI) with gene-modified autologous γδ T cells in patients with newly diagnosed glioblastoma multiforme (GBM) receiving maintenance temozolomide (TMZ).
Authors: Louis B. Nabors, Mina Lobbous, Lawrence S. Lamb, Kate Rochlin, Thriumaine Pillay, Samantha Youngblood, Mariska ter Haak, Trishna Goswami
Journal: Journal of Clinical Oncology (2022)

2044 Background: γδ T cells, MHC unrestricted immune cells, target NKG2D ligands differentially expressed on tumor cells. DeltEx drug resistant immunotherapy (DRI), a novel ex vivo expanded, activated γδ T cell expresses MGMT, conveying TMZ resistance. NCT04165941 , a phase 1 trial assessing the safety of single and multiple infusions of autologous DeltEx DRI cells presents updated safety and efficacy data. Methods: Adult newly diagnosed GBM patients with adequate organ function and KPS≥70% are enrolled. Cells engineered from apheresis after tumor resection were infused through a Rickham catheter placed during surgery. Cohort (C) 1, 2 and 3 receive 1, 3 and 6 doses of cells respectively on day (D) 1 of each 28-day maintenance cycle. Patients receive 1 x 10 7 γδ T cells intratumorally on D1 with 150 mg/m 2 of TMZ intravenously with the Stupp regimen. Primary endpoint is safety; secondary endpoints include progression free and overall survival. Immunologic and genomic correlative analyses are being conducted. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade 3 cardiopulmonary or hepatic toxicity, grade 4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. Results: 12 patients (58% male; median age 66.5 (range: 21-76); 66.7% IDH-WT, 66.7% MGMT unmethylated) were enrolled with 6 dosed (3 in C1, 3 in C2). No patients had DLTs, cytokine release syndrome (CRS), or neurotoxicity. The most common adverse events (AEs) were Grade 1/2 events including fever, leukopenia, nausea, and vomiting attributable to TMZ or radiotherapy. One subject had Grade 3 treatment related AEs of UTI, dehydration, and thrombocytopenia. Three evaluable C1 patients have PFS of 8.3, 11.9, 7.4 months and OS of 15.6, 17.7 and 9.6 months respectively. In C2, three patients have been dosed, with one patient with stable disease at 8.2 months after receiving all three doses and no DLTs. Patient recruitment continues with anticipated completion in 2022. Conclusions: Data demonstrates that single, repeat doses of DRI T cells have manageable toxicity with encouraging trend in PFS.
Long-term utilization and benefit of luspatercept in patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) from the MEDALIST trial.
Authors: Pierre Fenaux, Valeria Santini, Rami S. Komrokji, Amer Methqal Zeidan, Guillermo Garcia-Manero, Rena Buckstein, Dimana Miteva, Karen Keeperman, Natalia Holot, Jennie Zhang, Christina Hughes, Barbara Rosettani, Aylin Yucel, Uwe Platzbecker
Journal: Journal of Clinical Oncology (2022)

7056 Background: Luspatercept was previously shown to improve anemia in the phase 3 MEDALIST trial of pts with LR-MDS ineligible, intolerant, or refractory to erythropoiesis-stimulating agents (ESAs). Here, we report the long-term clinical value of luspatercept treatment (Tx) in pts from the MEDALIST study including dosing and rates of progression to acute myeloid leukemia (AML) and high-risk MDS (HR-MDS). Methods: Eligible pts were ≥ 18 y of age, had LR-MDS requiring regular red blood cell (RBC) transfusions, and were ineligible/intolerant or refractory to ESAs. Pts were randomized 2:1 to subcutaneous luspatercept or placebo every 3 wk for 24 wk. The primary endpoint was RBC transfusion independence (RBC-TI) ≥ 8 wk during wk 1–24. MEDALIST pts were eligible for enrollment into the long-term follow-up study. Median duration of Tx and cumulative duration of response were determined by Kaplan–Meier (KM) analysis. Total person-years for pts at risk of HR-MDS/AML progression was calculated from LR-MDS diagnosis to HR-MDS/AML diagnosis, or to last HR-MDS/AML follow-up date for pts who did not progress. Results: As of January 15, 2021, the median duration of Tx was 11.70 (95% CI, 8.97–16.33) mo for luspatercept pts and 5.52 (95% CI, 5.52–5.59) mo for placebo pts. Of those enrolled in MEDALIST, 106/153 (69.3%) pts receiving luspatercept and 64/76 (84.2%) receiving placebo escalated to the maximum dose of 1.75 mg/kg. During the entire Tx phase, RBC-TI ≥ 8 wk was observed in 74/153 (48.4%) and 12/76 (15.8%) pts in the luspatercept and placebo arms, respectively, with a median cumulative duration of response of 80.7 (95% CI, 53.71–154.14) wk and 21.0 (95% CI, 10.86–NE) wk, respectively. During the entire Tx period, RBC-TI ≥ 16 wk was observed in 48/153 (31.4%) and 6/76 (7.9%) pts in the luspatercept and placebo arms, respectively (Table). Among pts randomized to luspatercept, 13/153 (8.5%) progressed to HR-MDS/AML during the entire Tx period, compared with 5/76 (6.6%) for placebo. The total person-years for pts randomized to luspatercept at risk of progressing to HR-MDS/AML was 401.7 y vs 190.9 y for placebo. Conclusions: Pts receiving luspatercept had an extended period of clinical benefit and &gt; 50% of pts continued to receive luspatercept for &gt; 1 y, the majority of whom underwent dose escalations to achieve an optimal response. Pts experienced durable responses with luspatercept, with a median cumulative duration of RBC-TI response of approximately 20 mo. Pts receiving luspatercept also appeared to have a longer time to HR-MDS/AML progression than those receiving placebo.[Table: see text]
Cemiplimab in advanced cutaneous squamous cell carcinoma: A real-world experience of outcomes and safety.
Authors: Sunil Badami, Anita Mazloom, John Harrison Howard, J. Spencer Liles, Omar Alkharabsheh, Brian Edward Persing, Daniel Cameron, Adam Huddleston, Robert Gilbert, Kshithi Venkatesh, Pranitha Prodduturvar
Journal: Journal of Clinical Oncology (2022)

e21545 Background: Nearly 1.5 million cases of cutaneous squamous cell cancer (cSCC) are diagnosed annually in the United States. Approximately 1% of cases are in the advanced unresectable stage. The standard of care in unresectable advanced disease is immunotherapy with anti-PD-1 agents. Cemiplimab, an anti-PD-1 antibody, was approved by the Food and Drug Administration in 2018. We present real-world clinical data from a single institution on outcomes and safety for patients treated with cemiplimab for metastatic and unresectable cSCC. Methods: We conducted a retrospective cohort analysis of patients treated with cemiplimab (350 mg every 3 weeks) for advanced cSCC from September 2018 until December 2021. Data included patient demographics, tumor characteristics, and treatment course. Patients who received at least 1 dose of cemiplimab and one clinic follow-up were included for analysis. Clinical response and adverse events (AE) were evaluated. Results: Of the 26 patients treated, 84% were male (n = 22), and 16% were female (n = 4) with a median age of 74 years (39-94). Twenty-three (23) patients were included in the final analysis as 3 patients transferred care to an outside facility and were not available for follow-up. Nineteen (19) patients (73%) had locally advanced disease and 7 (27%) had metastatic disease. The most common site of the primary tumor was head/neck (85%, n = 22) with all remaining cases on the trunk/extremities (15%, n = 4). Patients received a median of 7 doses of cemiplimab (range 1- 46). The median time to first response was 1.7 months which required a median of 2.5 doses. An objective clinical response defined as complete response (CR) or partial response (PR) was seen in 18/23 (78%) patients, of whom 8/23(35%) were CR and 10/23 (44%) PR. The ongoing response was noted in 6/23 (27%) with continued treatment. Treatment was well-tolerated with 6/23 (26%) adverse events (AE) all of which were grade 1 or 2: 1 (4%) grade 1 pruritus, 5 (21.7%) grade 2. Of the 5 grade 2 AEs, 1 was infusion-related, 2 hypothyroidism, 1 dermatitis, 1 rheumatoid arthritis flare. No grade 3-5 AEs were noted. Conclusions: To the best of our knowledge, this is the first real-world outcomes study of advanced cSCC patients treated with cemiplimab in the United States. The overall efficacy, response rate, and safety profile were better in comparison to the results of the EMPOWER-CSCC-1 trial.[Table: see text]
The landscape of KDM5A mutations and hotspots in Chinese patients with solid tumors.
Authors: Ke Li, Zhe He
Journal: Journal of Clinical Oncology (2022)

e15115 Background: As a kind of histone modification enzyme, Lysine-specific demethylase can eliminate di- and tri-methyl groups from lysine 4 of histone. A growing number of shreds of evidence demonstrate that the disfunction of KDM5A relates closely to the initiation and progression of various diseases, particularly cancers, including but not limited to breast cancer, prostate cancer, glioblastoma, etc. However, research on the mutation spectrum of KDM5A in Chinese cancer patients is lacking. Methods: Ranging from Jan 14, 2020, to Oct 25, 2021, genomic DNA extracted from 5419 blood or tissue samples involving more than 22 solid tumors types were analyzed by NGS assay to investigate the landscape of KDM5A mutations and hotspots. Results: KDM5A somatic mutations existed in approximately 6.50% of all samples and almost all kinds of screened cancer types, among which, endometrial cancer comes first with the highest mutational frequency up to 21.05%, followed by the esophagus and esophagogastric junction cancer (18.18%) and bladder cancer (12.50%). Further analysis was conducted to explore mutational hotspots in KDM5A. Although almost 150 mutation sites existing in KDM5A had been identified in our research, the most prominent mutational hotspots are G1200, T30, M766, occupying 19.63%, 17.51%, and 6.37% of all SNV and Indel KDM5A mutations, respectively. Conclusions: Our study partially disclosed the panorama of the KDM5A mutational landscape in Chinese patients with solid tumors for the first time. Further studies with larger samples and populations are much needed to enhance our understanding of this enzyme in cancer biology.
BRCAAWAY: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) with DNA repair defects.
Authors: Maha H. A. Hussain, Masha Kocherginsky, Neeraj Agarwal, Jingsong Zhang, Nabil Adra, Channing Judith Paller, Joel Picus, Zachery R Reichert, Russell Zelig Szmulewitz, Scott T. Tagawa, Young E. Whang, Robert Dreicer, Timothy Kuzel, Latifa Bazzi, Travis A. Gerke, Stephanie Daignault-Newton, Arul Chinnaiyan, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2022)

5018 Background: The PARP-inhibitor olaparib is approved for mCRPC patients (pts) with deleterious germline or somatic homologous recombination repair gene mutations (HRRm). PARP1 interacts with androgen signaling, and castration-resistant tumor cells exhibit increased PARP1 activity. Preclinically PARP1-inhibition synergizes with androgen receptor (AR) targeted therapy. BRCAAway is a biomarker selected, randomized, open-label, multicenter phase 2 trial evaluating efficacy of targeting AR vs PARP vs combination in first line mCRPC patients with germline and/or somatic HRRm in BRCA1, BRCA2, or ATM. Methods: Eligible mCRPC pts underwent tumor next generation sequencing and germline testing. Pts with inactivating BRCA1, BRCA2 and/or ATM alterations were randomized 1:1:1 to Arm 1 abiraterone (1000 mg daily) + prednisone (5mg bid) (Abi/pred), Arm 2 olaparib (300 mg bid) or Arm 3 olaparib + Abi/pred. The primary end point is progression-free survival (PFS) analyzed using Kaplan-Meier estimates and Cox regression. Secondary endpoints include measurable disease response rate (RR) by RECIST, PSA-RR, undetectable PSA (≤ 0.2 ng/ml) and toxicity. Arms 1 and 2 pts were allowed to cross over at progression. Pts with other HRRm were treated with olaparib; Arm 4 (ongoing). Results: 161 pts were registered and had NGS testing; 60 pts were randomized to Arms 1-3; to date 59 are evaluable for toxicity and 53 are evaluable for PFS. Baseline median age 67 (range 42-85) years; 54 pts were White, 6 were Black; sites of disease: bone only (n=31), soft tissue only (n=18), bone and soft tissue (n=10); median PSA 14.61 ng/ml (range 0.15-4036.8). Mutational status: BRCA1 only n = 2, BRCA2 only n = 39, ATM only n = 8, and &gt; 1 HRRm n = 11. 34 pts had germline and 26 had somatic mutations. Median (range) follow-up time: 8.3 (0.8, 33.3), 12.2 (2.7, 21.8) and 16.8 (2.9, 41.7) months in Arms 1, 2 and 3. 43 pts had treatment-related adverse events; most common were fatigue (23 pts; 1 Grade (G) 3, 22 G1/2), nausea (17 pts, G1/2), and anemia (9 pts, 2 G3, 7 G1/2). ≥50% PSA decline was 79%, 67%, and 85% of pts in Arms 1, 2, and 3, respectively. Median PSA nadir (ng/mL) (95% CI) Arms 1-3: 2.17 (0.44, 49.27), 3.10 (0.83, 12.01), and 0.50 (0.10, 2.13), respectively. Undetectable PSA, median PFS, and 12-month PFS by Arm are listed in the table. Conclusions: In mCRPC pts with inactivating BRCA1, BRCA2 and/or ATM alterations Abi/pred + olaparib was well tolerated and resulted in longer PFS and better PSA response vs either agent alone. Clinical trial information: NCT03012321. [Table: see text]
Early mortality in epithelial ovarian cancer.
Authors: Erin McMinn, Dimitrios Nasioudis, Nawar A. Latif, Lori Cory, Emily Meichun Ko, Robert Giuntoli
Journal: Journal of Clinical Oncology (2022)

e17585 Background: Investigate the prevalence and characteristics of patients with epithelial ovarian carcinoma (EOC) who experience early mortality defined as death within 90 days of diagnosis. Methods: The National Cancer Database was accessed, and patients diagnosed with a pathologically confirmed EOC between 2004-2015 were identified. Patients who died within 90 days from diagnosis were identified. Clinico-pathological characteristics were compared with the chi-square and Mann Whitney U test. Results: A total of 150064 patients diagnosed with EOC were identified; 13561 (9%) patients died within 90 days from diagnosis with a decreasing incidence per year of diagnosis (from 9.8% in 2004 to 8% in 2015). These patients were older (median 76 vs 61 years, p &lt; 0.001), more likely to be Black (11.4% vs 7.1%, p &lt; 0.001), have government-issued insurance (75.6% vs 45.4%, p &lt; 0.001), median income &lt; 48000$ (45.1% vs 37.9%, p &lt; 0.001), comorbidities (35% vs 19.1%, p &lt; 0.001), reside closer to treatment facility (median 8 vs 12.3 miles, p &lt; 0.001) and present to non-academic facilities (68.5% vs 58.1%, p &lt; 0.001). Incidence of early mortality was 3.6% for patients aged &lt; 65 years, 11.2% for those 65-79 years and 28.6% among those &gt; = 80 years. For patients who experienced early mortality, 6067 (44.7%) did not receive any treatment, 2969 (21.9%) received chemotherapy only, 3345 (24.7%) underwent surgery only and 1180 (8.7%) received both. The rate of patients who did not receive any treatment was higher for patients aged &gt; = 80 years (25.6%) compared to those aged 65-79 (6.9%) and &lt; 65 years (2.5%), p &lt; 0.001. For patients who underwent surgery, median inpatient stay was 9 days while unplanned readmission rate within 30-days from discharge was 10.8%. After controlling for insurance, type of treatment facility, comorbidities, income, race, and stage, octogenarians had higher odds of early mortality (OR 6.02, 95% CI: 5.65, 6.41) compared to those aged &lt; 65 years. Higher odds of early mortality were also observed among octogenarians who received chemotherapy (OR 4.28, 95% CI: 3.84, 4.77) or surgery (OR 5.72, 95% CI: 5.15, 6.35) compared to those &lt; 65 years, after controlling for the aforementioned confounders. Conclusions: Approximately 1 in 10 patients diagnosed with ovarian cancer will expire within 90 days from diagnosis. These patients are older and more likely to have medical comorbidities. More than 1 in 4 octogenarians with ovarian cancer will die within 90 days of diagnosis. Some of these patients may not be candidates for active treatment; however, interventions that facilitate timely presentation, target frailty, and allow medical optimization are greatly warranted.
Investigation of the <i>DPYD, TYMS, ENOSF1, MTHFR, CDA, CES2,</i> and <i>UGT1A1</i> genes in patients who developed fatal fluoropyrimidine-associated toxicity in Northern Brazil.
Authors: Marianne R. Fernandes, Danielle Feio da Costa, Williams Fernandes Barra, Juliana Carla Gomes Rodrigues, Millene Arruda Bechara Gonçalves, Raiza Martins Fontoura, Francisco Cezar Aquino de Moraes, Esdras Edgar Batista Pereira, Rommel Mario Rodriguez Burbano, Paulo Pimentel Assumpção, Ana Latorre-Pellice, Olalla Maroñas Amigo, Raquel Cruz Guerrero, Sidney Emanuel Batista dos Santos, Ángel María Carracedo Álvarez, Ney Pereira Carneiro dos Santos
Journal: Journal of Clinical Oncology (2022)

e15532 Background: Fluoropyrimidine-based treatments are still considered challenging due to the wide variability in efficacy and toxicity rates presented by patients. This variability can be explained, partially, by individual genetic differences that contribute significantly to the response of the drug, with 30% of patients experiencing severe toxicity related to dihydropyrimidine dehydrogenase (DPD) deficiency and 5-Fluorouracil (5-FU) metabolism. Methods: This study analyzed the exome of the main genes involved in the fluoropyrimidine metabolism pathway ( DPYD, TYMS / ENOSF1, MTHFR, CDA, CES2, and UGT1A1) in seven patient who developed fatal 5-FU toxicity diagnosed with gastric or colorectal adenocarcinoma and underwent fluoropyrimidine-based cancer treatment. The genotyping service was carried out at CEGEN-PRB3-ISCIII; it is supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. Results: A total of 74 genetic polymorphisms were identified, 25 of which stand out due to their potential role in the safety of 5-FU administration. Eight variants are exclusive of the studied population (two found in the DPYD gene, two in the MHFR, one in the CES2, and three in the UGT1A1 gene) and 17 have already been associated with fluoropyrimidine efficacy and/or toxicity events: 10 of them are located in the DPYD gene (rs1801159, rs2297595, rs72728438, rs17376848, rs1801160, rs1801265, rs22447512, rs5568, rs56038477, rs56276561, and rs56293913), two in the intergenic region of the TYMS/ ENOSF1 genes (rs11280056 and rs699517), two in the MTHFR gene (rs1801131 and rs1801133) and three in the CDA gene (rs1048977, rs2072671, and rs3215400). Conclusions: The current study has allowed us to obtain a global profile of genetic variants in the pharmacokinetic and pharmacodynamic pathways of fluoropyrimidines in patients with high genetic miscegenation in the northern region of Brazil who have evolved to death due to the fatal toxicity resulting from 5-FU-based therapies. Keywords: Pharmacogenomics; Exome; 5-Fluorouracil; Drug toxicity; Brazil.
TIRA study: A phase III, multicenter, randomized controlled study of toripalimab plus radical chemoradiotherapy with or without concurrent cisplatin in patients with high-risk locoregionally advanced nasopharyngeal carcinoma.
Authors: Cheng Xu, Jun Ma
Journal: Journal of Clinical Oncology (2022)

TPS6101 Background: Patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) suffer a high risk of distant metastasis and require guideline-recommended multimodality therapy. However, cisplatin-based concurrent chemotherapy leads to a high incidence of severe toxicities and low patient compliance, consequently limiting survival improvement. Toripalimab, an immune checkpoint inhibitor targeting programmed cell death 1 (PD-1), has a novel anti-cancer mechanism and mild toxicity spectrum. Robust evidence showed that given toripalimab + gemcitabine-cisplatin (GP) chemotherapy regimen, the median progression-free survival could be markedly improved in patients with recurrent and metastatic NPC. Besides, PD-1 antibody + radiotherapy is also regarded as a promising therapeutic strategy due to the synergistic effect. Therefore, we hypothesized that the de-intensification strategy using toripalimab + induction chemotherapy (IC) followed by radiotherapy alone would obtain equivalent survival and low toxicity in patients with LA-NPC compared with toripalimab + IC followed by concurrent chemoradiotherapy. Methods: TheTIRA study is a multicenter, randomized, controlled, open-label, phase III study. Since August 2021, we have been recruiting high-risk LA-NPC patients (stage III-IVa, except T 3-4 N 0 M 0 &amp; T 3 N 1 M 0 ) from 12 Chinese centers. Our target sample size is temporarily set at 494 patients with 247 for each arm. Patients will be 1:1 ratio randomized to the experimental or control arm. Patients in the experimental arm will receive induction-concurrent toripalimab (240 mg, d1, Q3W × 6 cycle) with IC (gemcitabine 1000 mg/m 2 , d1 &amp; d8 + cisplatin 80 mg/m 2 , d1, Q3W × 3 cycle) + intensity-modulated radiotherapy (IMRT, 70 Gy in 33 fractions), and thereafter adjuvant toripalimab (240 mg, d1, Q3W × 11 cycle). Patients in the controlled arm will receive an additional concurrent cisplatin (100 mg/m 2 , d1, Q3W × 2 cycle). The primary endpoint is the 3-year failure-free survival. Secondary endpoints include 3-year overall survival, 3-year distant metastasis-free survival, 3-year locoregional recurrence-free survival, quality-of-life assessment according to the systems of the European Organization for Research and Treatment of Cancer and the Functional Assessment of Cancer Therapy, and safety profile. Exploratory analysis will be performed for potential biomarkers of survival prediction including PD-L1 expression and tumor-infiltrating lymphocytes. Clinical trial information: NCT04907370.